Compositions and methods for enhancing corticosteroid delivery

ABSTRACT

The present invention comprises a composition, method of enhancing potency and method of delivering corticosteroids in a vehicle comprising at least two penetration enhancers, and solvents and emulsifiers. The propylene glycol and penetration enhancers are present in ratio to the total of the propylene glycol, penetration enhancers, and solvents and emulsifiers of at least about 0.70.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 10/037,360,filed Dec. 21, 2001, which is incorporated herein by reference.

FIELD OF THE INVENTION

Topical corticosteroids are useful for their anti-inflammatory,anti-pruritic and vasoconstrictive actions. Corticosteroids (orcorticoids) are any steroids (lipids that contain a hydrogenatedcyclopentoperhydrophenanthrene ring system) elaborated by the adrenalcortex (except sex hormones of adrenal origin) in response to therelease of adrenocorticotrophin or adrenocorticotropic hormone by thepituitary gland, or to any synthetic equivalent, or to angiotensin H.Corticosteroids include but are not limited to alclometasonedipropionate, amcinonide, amcinafel, amcinafide, beclamethasone,betamethasone, betamethasone dipropionate, betamethasone valerate,clobetasone propionate, chloroprednisone, clocortelone, cortisol,cortisone, cortodoxone, difluorosone diacetate, descinolone, desonide,defluprednate, dihydroxycortisone, desoximetasone, dexamethasone,deflazacort, diflorasone diacetate, dichlorisone, esters ofbetamethasone, flucetonide, flucloronide, fluorocortisone, flumethasone,flunisolide, fluocinonide, fluocinolone acetonide, flucortolone,fluperolone, fluprednisolone, fluoroandrenolone a cetonide, fluocinoloneacetonide, flurandrenolide, fluorametholone, fluticasone propionate,hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate,hydrocortamate, medrysone, meprednisone, methylprednisone,methylprednisolone, mometasone furoate, paramethasone, prednisone,prednisolone, prednidone, triamcinolone acetonide, and triamcinolone.

Hydrocortisone was the first corticosteroid found to be topicallyeffective. Other more potent glucocorticoids, which are a subset ofcorticosteroids that affect carbohydrate metabolism, inhibitcorticotropin secretion, and possess pronounced anti-inflammatoryactivity, have since been developed. Currently, topical steroids areamong the most frequently prescribed of all dermatological drugproducts.

It is believed that glucocorticoids exert their potent anti-inflammatoryeffects by inhibiting the formation of prostaglandins and otherderivatives of the arachidonic acid pathway. It is known thatglucocorticoids inhibit the release of phospholipase A2, the enzymeresponsible for liberating arachidonic acid from cell membranes, thusinhibiting the arachidonic acid pathway. Currently, it is believed thatglucocorticoids inhibit phospholipase A2, in cells by directly inducingphosphorylation of the enzyme.

Steroids are commonly divided into two classes, fluorinated andnonfluorinated. Fluorinated steroids have been chemically modified toincrease potency. These modifications, such as halogenation andmethylation, can result in improved activity within the target cell andin decreased breakdown to inactive metabolites. These modifications canalso lead to more systemic side effects. However, modification of thechemical structure of the steroid is not the only way to increasepotency.

The potency of topical steroid preparations is strongly correlated totheir absorption through the skin. Treatment of the skin prior toapplication of the topical steroid may also affect the absorption of thecompounds into the skin. Treatments with keratolytics or with fatsolvents (such as acetone) disrupt the epidermal barrier and increasepenetration. Hydrating the skin has also been shown to increase thepenetration of the corticosteroids.

Once absorbed through the skin, topical corticosteroids are handledthrough pharmacokinetic pathways similar to systemically administeredcorticosteroids. The potencies of corticosteroids vary greatly and it isa challenge to increase the potency of any particular steroid.

BACKGROUND OF THE INVENTION

The clinical effectiveness of corticoids is related to four basicproperties: vasoconstriction, antiproliferative effects,immunosuppression, and anti-inflammatory effects. Topical steroids causethe capillaries in the superficial dermis to constrict, thus reducingerythema. The ability of a given glucocorticoid agent to causevasoconstriction usually correlates with its anti-inflammatory potency.Vasoconstrictor assays are used in the art and by the U.S. Food and DrugAdministration for determining the potency of topical corticosteroidpreparations. Topical glucocorticoid preparations have been divided inthe field into seven classes based on potency based on double-blindclinical studies and vasoconstrictor assays. Class 1 includes the mostpotent, while class 7 contains the least potent.

The following glucocorticoid preparations were designated inFitzpatrick, Dermatology in General Medicine, 5^(th) edition, CD-ROM,1999, Table 243-1, with the following classes.

TABLE 1 Corticosteroid Preparation Corticosteroid Class SourceTemovate ® Cream Clobetasone propionate 1 Glaxo Wellcome 0.05%Temovate ® ointment Clobetasone propionate 1 Glaxo Wellcome 0.05%Diprolene ® cream Betamethasone 1 Schering Corp. 0.05% dipropionateDiprolene ® ointment Betamethasone 1 Schering Corp. 0.05% dipropionatePsorcon ® ointment Diflorasone diacetate 1 Dermik Laboratories, Inc.Cyclocort ® ointment Amcinonide 2 Fujisawa 0.1% Diprolene ® cream AFBetamethasone 2 Schering Corp. 0.05% dipropionate Diprosone ® ointmentBetamethasone 2 Schering Corp. 0.05% dipropionate Elocon ® ointment 0.1%Mometasone furoate 2 Schering Corp. Florone ® ointment Diflorasonediacetate 2 Dermik 0.05% Halog ® cream 0.1% Halcinonide 2Westwood-Squibb Lidex ® gel 0.05% Fluocinonide 2 Medicis PharmaceuticalsCorp. Lidex ® cream 0.05% Fluocinonide 2 Medicis Pharmaceuticals Corp.Lidex ® ointment 0.05% Fluocinonide 2 Medicis Pharmaceuticals Corp.Maxiflor ® ointment Diflorasone diacetate 2 Allergan Herbert 0.05%Topicort ® cream 0.25% Desoximetasone 2 Medicis Pharmaceuticals Corp.Topicort ® gel 0.05% Desoximetasone 2 Medicis Pharmaceuticals Corp.Topicort ® ointment Desoximetasone 2 Medicis Pharmaceuticals Corp. 0.25%Aristocort A ® ointment Triamcinolone 3 Fujisawa 0.1% acetonideCutivate ® ointment Fluticasone propionate 3 Glaxo Wellcome 0.005%Cyclocort ® cream 0.1% Amcinonide 3 Fujisawa Cyclocort ® Lotion 0.1%Amcinonide 3 Fujisawa Diprosone ® cream Betamethasone 3 Schering Corp.0.05% dipropionate Florone ® cream 0.05% Diflorasone diacetate 3 DermikHalog ® ointment 0.1% Halcinonide 3 Westwood-Squibb Lidex ® E cream0.05% Fluocinonide 3 Medicis Pharmaceutical Corp. Maxiflor ® cream 0.05%Diflorasone diacetate 3 Allergan Herbert Valisone ® ointmentBetamethasone valerate 3 Schering Corp. 0.1% Cordran ® ointmentFlurandrenolide 4 Oclassen 0.05% Elocon ® cream 0.1% Mometasone furoate4 Schering Corp. Kenalog ® cream 0.1% Triamcinolone 4 Westwood-Squibbacetonide Synalar ® ointment Fluocinolone acetonide 4 MedicisPharmaceuticals Corp. 0.025% Westcort ® ointment Hydrocortisone 4Westwood-Squibb 0.2% valerate Cordran ® cream 0.05% Flurandrenolide 5Oclassen Cutivate ® cream 0.05% Fluticasone propionate 5 Glaxo WellcomeDiprosone ® lotion Betamethasone 5 Schering Corp. 0.05% dipropionateKenalog ® lotion 0.1% Triamcinolone 5 Westwood-Squibb acetonide Locoid ®cream 0.1% Hydrocortisone 5 Ferndale butyrate Synalar ® cream 0.025%Flucinolone acetonide 5 Medicis Pharmaceuticals Corp. Valisone ® cream0.1% Betamethasone valerate 5 Schering Corp. Westcort ® cream 0.2%Hydrocortisone 5 Westwood-Squibb valerate Aclovate ® cream 0.05%Alclometasone 6 Glaxo Wellcome dipropionate Aclovate ® ointmentAlclometasone 6 Glaxo Wellcome 0.05% dipropionate Aristocort ® cream0.1% Triamcinolone 6 Fujisawa acetonide Desowen ® cream 0.05% Desonide 6Galderma Synalar ® solution Fluocinolone acetonide 6 MedicisPharmaceuticals Corp. 0.01% Synalar ® cream 0.01% Fluocinolone acetonide6 Medicis Pharmaceuticals Corp. Tridesilon ® cream Desonide 6 Miles0.05% Valisone ® lotion 0.1% Betamethasone valerate 6 Schering Corp.Topicals with 7 hydrocortisone dexamethasone, flumethasone,prednisolone, and methylprednisolone

All percentages given are weight percentages unless otherwise noted.

Although there is no significant difference between potencies withinClass 2, within Class 1 Temovate® cream or ointment is significantlymore potent than Class 1 Diprolone® cream or ointment of Schering andClass 1 Psorcon® ointment of Dermik Laboratories, Inc.

Several factors such as the vehicle, the integrity of the epidermalbarrier, and the use of occlusive dressings affect the percutaneousabsorption and resulting potency of corticosteroids regardless of theintrinsic potency of the glucocorticosteroid (or glucocorticoid)molecule. Further, inflammation and/or other disease processes in theskin increase percutaneous absorption.

The vehicle in which the corticoid is incorporated may be as importantas the corticoid molecule itself in determining the potency of a givenformulation because the vehicle affects the amount of corticoid that isreleased in any given period of time, and its absorption. In manycorticosteroid compositions, the vehicle is as much as 99% of the totalcomposition. Very occlusive vehicles, such as ointments (water-insolublemixtures of oil and petrolatum), increase the corticosteroid effectbecause they provide increased hydration of the stratum corneum andincrease the skin's permeability. By covering the skin with a nocclusive dressing such as plastic wrap, this effect c an be heightenedas much as 100-fold. The solubility of the corticoid in the vehicle alsoaffects penetration into the skin.

Creams, which are suspensions of oil in water, have also been used asvehicles for corticosteroids. The compositions of creams vary and arefar less greasy than ointments but do not provide the same degree ofhydration to the skin, and therefore may not have as high penetration asointments. Lotions, which are suspensions of oil in water and aresimilar to creams, are vehicles which include agents to help solubilizethe corticosteroids. Solutions have been used as vehicles and are waterbased with propylene glycol. Gels are solid components at roomtemperature but melt on the skin. Lotions, gels and solutions have lesspenetration than ointments.

Many vehicles for corticosteroids include propylene glycol fordissolving the corticosteroid in the vehicle. In general, compositionsthat contain higher amounts of propylene glycol tend to be more potent.

Vehicles are so important in the potency of corticosteroids thatdifferent formulations containing the same amount of the samecorticosteroid often are in different potency classes. For example,commercially available preparations of 0.05% betamethasone dipropionateare classified as having Class 1, Class 2 or Class 3 potency, dependingon their vehicles (as seen in Table 1).

SUMMARY OF THE INVENTION

The present invention comprises a novel vehicle which is safe fortopical application, stable, and provides increased potency forcorticosteroid preparations, especially fluorinated corticosteroids.

An embodiment of the present invention delivers the corticosteroid in avehicle that comprises a corticosteroid, and (a) at least twopenetration enhancers, including propylene glycol, dimethyl isosorbideor diisopropyl adipate, (b) solvents and/or emulsifiers for thecorticosteroid and optionally the penetration enhancers and (c)optionally, non-solvent/emulsifier ingredients. The vehicle has a ratioof a:(a+b) that is greater than or equal to 0.70, preferably greaterthan or equal to 0.80 and most preferably greater than or equal to 0.90or 0.95.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention enhances the potency of corticosteroidpreparations with a vehicle comprising at least two penetrationenhancers, including diisopropyl adipate, dimethyl isosorbide, propyleneglycol, 1,2,6-hexanetriol, and benzyl alcohol. The corticosteroids withwhich this invention may be used include, but are not limited to,fluorinated corticosteroids.

Another embodiment of the present invention is a method for enhancingthe potency of corticosteroids, preferably fluorinated corticosteroids.The corticosteroid is combined with two or more penetration enhancers(preferably propylene glycol and at least one other penetrationenhancer), and one or more solvents and emulsifiers for thecorticosteroid and optionally penetration enhancers, wherein thepenetration enhancers are present in ratio to the total of thepenetration enhancers, and solvents and emulsifiers of at least about0.70, preferably at least 0.80 and most preferably 0.90 or 0.95.Optionally, one or more inactive ingredients may also be combined withthe corticosteroid.

Another embodiment of the present invention is a method of deliveringcorticosteroids to skin, nails or hair, preferably mammalian skin, mostpreferably human, dog or cat skin. The corticosteroids are preferablyfluorinated corticosteroids. The corticosteroid is combined with two ormore penetration enhancers, and one or more solvents and emulsifiers forthe corticosteroid, wherein the penetration enhancers are present inratio to the total of the penetration enhancers, and solvents andemulsifiers of at least about 0.70, preferably at least 0.85 and mostpreferably 0.90 or 0.95. Optionally, one or more inactive ingredientsmay also be combined with the corticosteroid.

As indicated above, this invention is broadly applicable tocorticosteroids in general, and fluorinated corticosteroids inparticular, most preferably fluocinonide or fluocinolone acetonide. Thefollowing examples show its application to preparations of fluocinonide,a commonly used fluorinated corticosteroid. Fluocinonide is acorticosteroid which is the 21-acetate ester of fluocinolone acetonidewith the chemical name pregna-1,4-diene-3,20-dione,21-(acetyloxy)-6,9-difluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(6α,11β,16α)-. Compositions containing 0.05% (all percentages are weightpercentages) fluocinonide are commonly classified as Class 2.

Example 1

Experiments were conducted with embodiments of the present invention andseveral control compositions. Compositions w ere prepared and theinvestigator was blinded with respect to the compositions. Thirty-sixhealthy volunteers were enrolled for two-day trials. On day 1, a singleapplication of approximately 10 milligrams of at least eightcompositions was made to 1 cm² sites on the lower aspect of eachvolunteer's forearms in accordance with a computer generatedrandomization code. After applying the compositions, the sites wereprotected using a raised perforated guard. The guard was secured to thearm with a non-occlusive tape and the subjects were scheduled to returnthe following day after being instructed to keep the sites dry.

After approximately 16 hours of contact with the skin, the protectiveguards were removed and the compositions were removed from the testsites by gently washing with mild soap and water. Skin vasoconstrictorevaluations were performed on a four point scale (0-3) at approximately18 hours after application.

Scores for skin vasoconstriction were summed for each composition (eachcomposition was applied to thirty-six volunteers and those thirty-sixscores were summed). For each composition tested, the ratio ofpenetration enhancers (a) to the sum of penetration enhancers, andsolvents and emulsifiers (a+b) was calculated (a:(a+b)). All of thecompositions comprise 0.10% fluocinonide.

TABLE 2 Range of a: (a + b) 1-0.95 0.94-0.90 0.89-0.80 0.79-0.700.69-0.60 0.59-0.50 Average of Summed 93 85 71 72 62 58 VasoconstrictorScores * means there were no samples with the range of 0.59 to 0.55.

As seen in the above table, the average vasoconstrictor scores aresignificantly lower for ranges of a:(a+b)<0.70. The corticosteroidpreparations with average vasoconstrictor scores of 58 and 62 aresignificantly less potent than those preparations with averagevasoconstrictor scores of 72 and higher. Scores of 62 and 58 are notsignificantly different. This magnitude of increase in vasoconstrictorscores is typical of an increase in class.

Several control compositions (with 0.10% fluocinonide and no penetrationenhancers, as defined below, were included) were also tested for theirvasoconstrictor scores in the same manner. Therefore, the ratios ofa:(a+b) are zero. The vasoconstrictor scores are 60.00 and 59.00, whichare significantly lower than the present invention's embodiments'vasoconstrictor scores.

Additionally, several other control compositions were tested for theirvasoconstrictor scores (“vasoscores”). These compositions comprised0.10% fluocinonide, and no diisoproyl adipate, propylene glycol ordimethyl isosorbide. Their vasoscores were 49.00, 47.00 and 44.00.

The experiments also included several Class 1 compositions as comparisonpoints. Psorcon® ointment by Dermik Laboratories, Inc. of Collegeville,Pa. with 0.05% diflorasone diacetate had a vasoscore of 101. Ultravate®ointment by Westwood-Squibb of Evansville, Ind. with 0.05% halobetasolpropionate had a vasoscore of 97, while Ultravate® cream byWestwood-Squibb with 0.05% halobetasol propionate had a vasoscore of 92.

In the ratio of (a):(a+b), penetration enhancers include at least twoof: propylene glycol, diisopropyl adipate, dimethyl isosorbide, 1,2,6hexanetriol, and benzyl alcohol (collectively referred to as “a”). Thesolvents and emulsifiers for the corticosteroid include one or more ofdehydrated alcohol, alcohol (95% v/v) USP, 3-Cyclohexene-1-Methanol,∝-4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citricacid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol,Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60,potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitanstearate, and 1,2,3-Propanetriol Ester (collectively referred to as“b”).

The compositions optionally comprise non-solvent/emulsifier ingredients,such as Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980,cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose,hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineraloil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF,purified water, stearyl alcohol, white petrolatum, and white wax.

The combination of penetration enhancers used in the invention have aremarkable and unexpected result. Compounds using similar concentrationsof a single penetration enhancer (e.g. propylene glycol as the solepenetration enhancer with 0.10% fluocinonide yielded vasoscores of72.00, and 50.00, depending on the solvents, emulsifiers andnon-solvent/emulsifier ingredients used) do not have similarly high vasoscores. Compositions with the combination of penetration enhancers andformula scores of less than 0.65 also have low vaso scores. Thereforethe invention results in an unexpected increase in potency of thefluocinonide.

Example 2

One embodiment of the present invention is detailed in the chart below.

TABLE 3 Component % w/w % w/w Fluocinonide 0.1 0.1 Micronized, USPPropylene Glycol, 70.0 74.9 USP Dimethyl isosorbide 15.0 DiisopropylAdipate 3.0 Isopropyl Myristate, 5.0 NF 1,2,6 2.5 TrihydroxyhexaneCarbopol 980 1.2 1.0 Diisopropanolamine 1.2 1.0 85%:propylene glycol(1:9) Citric Acid, USP 0.01 0.01 Purified Water, USP 2.49 2.49 Glyceryl2.5 2.5 monostearate Glyceryl 7.5 7.5 monostearate & PEG stearate

Example 3

Another embodiment of the present invention is detailed in the chartbelow.

TABLE 4 Component % w/w % w/w Fluocinonide 0.1 0.1 Micronized, USPPropylene Glycol, 66.8 69.9 USP Dimethyl isosorbide 5.0 DiisopropylAdipate 2.0 Isopropyl Myristate, 5.0 5.0 NF Carbopol 980 0.5 0.5Diisopropanolamine 0.5 0.5 85%:propylene glycol (1:9) White Petrolatum,5.0 5.0 USP Glyceryl 6.0 6.0 monostearate PEG 100 stearate 6.0 6.0Stearyl alcohol, NF 5.0 5.0 Sodium Lauryl 0.1 Sulfate, NF

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are evident from a review of thefollowing claims.

1-60. (canceled)
 61. A composition consisting essentially of: One or more corticosteroids, Two or more penetration enhancers selected from the group consisting of diisopropyl adipate, dimethyl isosorbide, propylene glycol, 1,2,6-hexanetriol, and benzyl alcohol; One or more of the group consisting of solvents and emulsifiers, and One or more of group consisting of non-solvent/emulsifier ingredients, and wherein the penetration enhancers are present in a ratio to a total of the penetration enhancers, and solvents and emulsifiers of at least about 0.9, and wherein the composition does not include a monoglyceride of a C₆-C₁₀ medium chain fatty acid.
 62. The composition of claim 61, wherein the corticosteroid is present at about 0.10%.
 63. The composition of claim 61, wherein the corticosteroid is present at about 0.50%.
 64. The composition of claim 61, wherein the corticosteroid is present at about 0.25%.
 65. The composition of claim 61, wherein the ratio is at least about 0.95.
 66. The composition of claim 61, wherein the corticosteroid comprises a fluorinated corticosteroid.
 67. The composition of claim 61, wherein the corticosteroid comprises fluocinonide.
 68. The composition of claim 61, wherein the corticosteroid comprises fluocinolone acetonide.
 69. The composition of claim 61, wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v) USP, 3-Cyclohexene-1-Methanol, .α.4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.
 70. The composition of claim 61, wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax. 